Although occasional instances of Oseltamivir resistance in the old H1N1 virus were reported prior to 2007, in nearly every case, it developed after a person was placed on the drug (due to so-called `spontaneous mutations’).

While of concern to the patient being treated, that happened in only
about 1% of treated cases, and studies suggested that these resistant
strains were `less biologically fit’, and were therefore thought unlikely to spread.

This resistance was due primarily to the acquisition of an H275Y mutation - where a single amino acid substitution (histidine (H) to tyrosine (Y)) occurs at the neuraminidase position 275 (Note: some scientists use 'N2 numbering' (H274Y)).

Had it not been replaced in the spring of 2009 with a new,NAI susceptible virus, treatment options for severe H1N1 influenza over the past seven years would have been substantially reduced.

We've been watching ever since 2009 for any signs that the new pH1N1 virus has been gaining resistance, but for the most part, the news has been pretty good.

Rates of resistant pH1N1 viruses have been low - around 1% - and like we saw prior to 2007, have generally been seen in (often immunocompromised) patients after they were placed on antivirals - again via `spontaneous mutations’.

And as before, these pH1N1 viruses carrying the H275Y mutation have been seen as taking a `fitness' hit, being less likely to transmit efficiently and spread widely.

All of which brings us to a new report, published today in the ECDC journal Eurosurveillance, which finds an elevated number of NAI resistant viruses with `permissive mutations' circulating in Japan, and describes the discovery of resistant pH1N1 carrying a G147R substitution that conferred resistance to both Oseltamivir and Peramivir.

An influenza A(H1N1)pdm09
virus carrying a G147R substitution in combination with an H275Y
substitution in the neuraminidase protein, which confers
cross-resistance to oseltamivir and peramivir, was detected from an
immunocompromised inpatient in Japan, March 2016.

This dual H275Y/G147R
mutant virus exhibited enhanced cross-resistance to both drugs compared
with the single H275Y mutant virus and reduced susceptibility to
zanamivir, although it showed normal inhibition by laninamivir.

While the bulk of this report centers around the discovery of a dual H275Y/G146R substitution in an immunocompromised patient while receiving peramivir treatment, the reports of clusters of regular H275Y (with permissive mutations) pH1N1 viruses circulating in Japan over the past couple of years are worth our attention as well.

A couple of excerpts from the Discussion follow (bolding mine), but you'll want to read the report in its entirety.

Discussion

The first widespread community cluster of the H275Y mutant A(H1N1)pdm09 virus was detected in Newcastle, Australia in 2011 [7].
The H275Y substitution in the NA protein would destabilise the mutant
virus. However, two additional V241I and N369K substitutions in the NA
of H275Y mutant viruses were reported to increase their replication and
transmission fitness, contributing to efficient transmission [8,9].

Indeed, during the 2013/14 influenza season, the H275Y mutant viruses
from a large community cluster in Hokkaido, Japan carried these
permissive substitutions. Following this finding, we subsequently
increased nationwide monitoring for the H275Y mutant viruses in the
2015/16 season and detected an H275Y mutant with V241I and N369K and an
additional G147R substitution in the NA protein from an
immunocompromised inpatient. The IC50 fold changes of a
number of NA inhibitors for the dual H275Y/G147R mutant virus compared
with those for the single H275Y viruses showed clearly the synergistic
effect of this dual substitution (Figure 2).

(SNIP)

Immunocompromised patients are at great risk
for emergence of the antiviral resistant virus because of the selective
pressure from prolonged exposure to antiviral drugs [16].
A high rate and prolonged shedding of the H275Y mutant A(H1N1)pdm09
virus in immunocompromised patients treated with oseltamivir and/or
peramivir were reported previously [17].
As a specimen from the husband of the patient was unavailable, we
cannot rule out that the patient was infected with a virus readily
carrying the G147R substitution. Results of this study nevertheless
suggest that this substitution likely occurred in the patient during
peramivir treatment. On the other hand, whether the H275Y mutation had
already occurred or not before infection remains unclear. Other
additional substitutions, I223R and S247N, in the NA protein of H275Y
mutant A(H1N1)pdm09 viruses have been reported and showed a synergistic
effect with the H275Y substitution on the reduction of NA inhibitor
susceptibility [18,19].

Although the frequencies of these dual substitutions were low, the
surveillance of antiviral-resistant viruses should be continued to
protect public health and support clinical management, particularly for
high risk populations.